Formulation and Characterization of Magnetic Nanoparticles Produced by Magnetotactic Bacteria for Medical Applications

La société Nanobactérie développe un traitement thermique innovant contre le cancer qui repose sur l‘utilisation de nanoparticules d‘oxyde de fer d‘origine bactérienne, appelées magnétosomes. Celles-ci sont injectées directement dans la tumeur puis activées par le champ magnétique alternatif. Cette activation crée une augmentation locale de la température provoquant la destruction de la tumeur, sans affecter les tissus sains environnants. Afin d‘éviter les problèmes de toxicité liés à la présence d‘endotoxines bactériennes à la surface des magnétosomes, un processus de purification est utilisé. Il permet l‘élimination de toute la membrane organique immunogène et de garder ainsi le minéral responsable de l‘activité thermique. Cependant, l‘élimination de cette membrane entraîne l‘agrégation des magnétosomes. La première étape de ce travail de thèse a donc consisté à stabiliser les magnétosomes purifiés, et l'‘identification du meilleur revêtement a été évaluée. Dans une deuxième partie, une nouvelle modalité de chauffage a été mise au point pour augmenter l‘efficacité de l‘hyperthermie magnétique dans la destruction de cellules cancéreuses.The Nanobactérie company develops a novel strategy of cancer treatment using iron oxide nanoparticles of bacterial origin, called magnetosomes. These nanoparticles are injected directly into the tumor and then activated by an alternating magnetic field. Activated nanoparticles trigger a highly localized rise of temperature, inducing the destruction of the tumor without any adverse effects on adjacent healthy tissues. To avoid the problems of toxicity caused by the presence of bacterial endotoxin which present on the surface of magnetosomes extracted from bacteria, a process of purification is realized to eliminate all the immunogenic organic membrane and keep only the mineral responsible for the thermal activity. However, since elimination of this membrane causes the aggregation of the magnetosomes which become unstable in aqueous solution, the first part of this work consisted in stabilizing the purified magnetosomes by a modification of their surface. The identification of the best coating was then evaluated. Moreover, in the second part of this work, a new heating modality was assessed to increase the efficiency of the magnetic hyperthermia in the destruction of cancer cells

Biocompatible coated magnetosome minerals with various organization and cellular interaction properties induce cytotoxicity towards RG-2 and GL-261 glioma cells in the presence of an alternating magnetic field

Abstract Background Biologics magnetics nanoparticles, magnetosomes, attract attention because of their magnetic characteristics and potential applications. The aim of the present study was to develop and characterize novel magnetosomes, which were extracted from magnetotactic bacteria, purified to produce apyrogen magnetosome minerals, and then coated with Chitosan, Neridronate, or Polyethyleneimine. It yielded stable magnetosomes designated as M-Chi, M-Neri, and M-PEI, respectively. Nanoparticle biocompatibility was evaluated on mouse fibroblast cells (3T3), mouse glioblastoma cells (GL-261) and rat glioblastoma cells (RG-2). We also tested these nanoparticles for magnetic hyperthermia treatment of tumor in vitro on two tumor cell lines GL-261 and RG-2 under the application of an alternating magnetic field. Heating, efficacy and internalization properties were then evaluated. Results Nanoparticles coated with chitosan, polyethyleneimine and neridronate are apyrogen, biocompatible and stable in aqueous suspension. The presence of a thin coating in M-Chi and M-PEI favors an arrangement in chains of the magnetosomes, similar to that observed in magnetosomes directly extracted from magnetotactic bacteria, while the thick matrix embedding M-Neri leads to structures with an average thickness of 3.5 µm2 per magnetosome mineral. In the presence of GL-261 cells and upon the application of an alternating magnetic field, M-PEI and M-Chi lead to the highest specific absorption rates of 120–125 W/gFe. Furthermore, while M-Chi lead to rather low rates of cellular internalization, M-PEI strongly associate to cells, a property modulated by the application of an alternating magnetic field. Conclusions Coating of purified magnetosome minerals can therefore be chosen to control the interactions of nanoparticles with cells, organization of the minerals, as well as heating and cytotoxicity properties, which are important parameters to be considered in the design of a magnetic hyperthermia treatment of tumor

Biocompatible Coated Magnetosome Minerals for Application in the Magnetic Hyperthermia Treatment of Tumors

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Biocompatible and stable magnetosome minerals coated with poly- l -lysine, citric acid, oleic acid, and carboxy-methyl-dextran for application in the magnetic hyperthermia treatment of tumors

International audienceMagnetic hyperthermia, in which magnetic nanoparticles are introduced into tumors and exposed to an alternating magnetic field (AMF), appears to be promising since it can lead to increased life expectancy in patients. Its efficacy can be further improved by using biocompatible iron oxide magnetosome minerals with better crystallinity and magnetic properties compared with chemically synthesized nanoparticles (IONP – Iron Oxide Nanoparticles). To fabricate such minerals, magnetosomes are first isolated from MSR-1 magnetotactic bacteria, purified to remove potentially toxic organic bacterial residues and stabilized with poly-L-lysine (N-PLL), citric acid (N-CA), oleic acid (N-OA), or carboxy-methyl-dextran (N-CMD). The different coated nanoparticles appear to be composed of a cubo-octahedral mineral core surrounded by a coating of different thickness, composition, and charge, and to be organized in chains of various lengths. The in vitro anti-tumor and heating efficacies of these nanoparticles were examined by bringing them into contact with GL-261 glioblastoma cells and by applying an AMF. This led to a specific absorption rate of 89–196 W gFe−1, measured using an AMF of 198 kHz and 34–47 mT, and to percentages of tumor cell destruction due to the exposure of the nanoparticles to the AMF of 10 ± 3% to 43 ± 3% depending on the coating agent. These results show the potential of this protocol for the tumor treatment by magnetic hyperthermia